Hypothalamic Protein Kinase C Regulates Glucose Production
Autor: | Tony K.T. Lam, Gary J. Schwartz, Luciano Rossetti, Carol K.L. Lam, Liora Caspi, Xiaosong Li, Madhu Chari, Evan D. Muse, Penny Y. T. Wang, Rachel A. Ross, Hiraku Ono, Roger Gutierrez-Juarez, Peter E. Light |
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Jazyk: | angličtina |
Rok vydání: | 2008 |
Předmět: |
Male
medicine.medical_specialty endocrine system Endocrinology Diabetes and Metabolism Hypothalamus 030209 endocrinology & metabolism Biology Carbohydrate metabolism Glibenclamide Diglycerides Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Enzyme activator 0302 clinical medicine KATP Channels Internal medicine Glyburide Internal Medicine medicine Animals Hypoglycemic Agents Channel blocker Benzopyrans Protein kinase C Protein Kinase C 030304 developmental biology 0303 health sciences Activator (genetics) Acetophenones Lipid metabolism Rats Enzyme Activation Protein Kinase C-delta Protein Transport Endocrinology Metabolism Glucose chemistry Rottlerin medicine.drug |
Zdroj: | Diabetes |
ISSN: | 1939-327X 0012-1797 |
Popis: | OBJECTIVE—A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K+ (KATP) channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of KATP channels remain unknown. RESEARCH DESIGN AND METHODS—To examine whether hypothalamic protein kinase C (PKC) mediates the ability of central nervous system lipids to activate KATP channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of KATP channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo. RESULTS—We first reported that direct activation of hypothalamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) suppressed glucose production. Coadministration of hypothalamic PKC-δ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-δ and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the KATP channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production. CONCLUSIONS—These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production. |
Databáze: | OpenAIRE |
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